Eosinophils are circulating leukocytes that contribute to a variety of diseases due to their pro- inflammatory function. Evidence is now accumulating linking eosinophils and their selective cytokines (eotaxins and IL-5) to Alzheimer's disease (AD) and related cognitive decline disorders. For example, eotaxin-1/CCL11 reversibly inhibits neural progenitor cell proliferation in vitro in isolated cells, neurospheres, and hippocampal cultures. Additionally, administration of plasma of aging mice or eotaxin-1/CCL11 to young mice decreases adult neurogenesis and impairs memory and learning, establishing a major potential role for this chemokine in the age- related decline of hippocampal function. There is even genetic evidence linking the CCL11 locus with susceptibility for early onset AD. Further support for the connection between eosinophils and AD is rendered by the association of IL-5 with the amyloid deposits of the brain tissues of AD patients. Human amylin has been shown to inhibit IL-5?mediated eosinophil survival and increase the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) by eosinophils following stimulation with calcium ionophore A23187. On the basis of these data, we have formulated the central hypothesis that CCL11 elicits increasing capacity to activate eosinophils as a function of the age of mice and man and that the mechanism involves an epigenetic response associated with histone 3 lysine 27 acetylation (H3K27ac). We will test the primary hypothesis by examining CCL11-mediated human and murine eosinophil activation and H3K27ac as a function of the age of the eosinophil donor and eosinophil lifespan. The studies proposed in this supplementary grant request are expected to advance our understanding of the emerging linkage between inflammation and aging. The results are expected to lay the foundation for understanding the association of eotaxin/CCL11 with cognitive decline, including Alzheimer's disease, which will hopefully be pursued in a future NIH R01 grant application. These results have potential direct implications for patients as there are a series of emerging biological agents that directly target eosinophils and their associated molecules, including antibodies against CCL11/eotaxin (bertalizumab) and IL-5 (benralizumab, antolamib, mepolizumab, and reslizumab).
The proposed research is relevant to public health because understanding the role of eosinophils and their selective cytokine (eotaxins and IL-5) in Alzheimer's disease (AD) is expected to lay the foundation for a new approach to treat AD and age-associated cognitive decline diseases. Thus, this proposal is relevant to the part of NIH's mission that pertains to fostering fundamental creative discoveries and innovative research strategies as a basis for ultimately protecting health.
|Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83|
|Grace, Jillian O; Malik, Astha; Reichman, Hadar et al. (2018) Reuse of public, genome-wide, murine eosinophil expression data for hypotheses development. J Leukoc Biol 104:185-193|
|Schwartz, Justin T; Morris, David W; Collins, Margaret H et al. (2018) Eosinophil progenitor levels correlate with tissue pathology in pediatric eosinophilic esophagitis. J Allergy Clin Immunol :|
|Fulkerson, Patricia C (2017) Transcription Factors in Eosinophil Development and As Therapeutic Targets. Front Med (Lausanne) 4:115|